Mitochondria are dynamic organelles known to be the key energy producer in cells and axons. Within the last 10 years there has been an explosion of research in a specific mitochondrial behavior called mitochondrial remodeling, referring to the activity of these organelles in fusing and dividing. The major new insight from these studies is that mitochondria are not only producing energy, but are involved in cell killing and cell rescue. A significant cell rescue function is the correction of errors in mitochondrial DNA by mitochondrial fusion. This grant allows, for the first time, application of this knowledge in mitochondrial remodeling to myelinated nerve biology. The key is a new technique that dynamically monitors mitochondrial fusion through collision of two color-coded mitochondrial populations in axons in vivo. This allows us to address three new areas in myelinated nerve biology with major implications in health and in disease. In the area of pathology, we will examine if stressful stimuli (nerve transection and demyelination) trigger myelinated axons to increase mitochondrial remodeling activity. This will lay the groundwork for future studies to see whether myelinated axons can repair their mitochondrial DNA damage locally through mitochondrial remodeling. In the area of physiology, we will examine if mitochondrial remodeling (fusion) contributes to metabolic matching in myelinated nerves through mitochondrial quality control. We will examine whether metabolically weak mitochondria can be locally rejuvenated through fusion with strong mitochondria, and whether mitochondrial fusion improves the quality of mitochondria recruited by the node of Ranvier during nerve activity. By pioneering a study of strictly local mitochondrial fusion in myelinated axons, we are tapping into an unexplored autonomous ability of axons that will stimulate research in multiple sclerosis (MS) towards a novel therapeutic direction. Can we boost axons to use mitochondrial fusion as a defense to repair mitochondrial DNA damage and slow nerve degeneration in this disease that strikes ~ 1 in 10,000 adults in the US?